The goals of this laboratory have been to understand the instantaneous, 3-D dynamic interactions between the elements of the mitral valvular-ventricular complex in order to define a mechanistic basis for proper mitral valve function. Having built a solid physiological foundation consisting of unique 3-D in vivo geometrical and LV mechanics functional data in intact animals, we now propose to characterize the abnormalities in mitral leaflet shape, motion, and coaptation which result in incomplete mitral leaflet closure (IMLC) and ischemic mitral regurgitation ("IMR"). This envisions the development of novel surgical reparative methods based on in vivo 3-D data analysis, which should lead to the rational creation of new and more effective surgical approaches to treat this common, serious, and challenging clinical disorder. The Specific Aims of the present application are to explore the validity of a new set of mechanisms suggested by our previous studies to be associated with IMLC and IMR, including assessment of 3-D motion of many parts of the valve leaflets. We will: 1. Describe the perturbations of the complex 3-D geometry of the mitral leaflets per se which cause IMR; 2. Characterize specific mechanisms responsible for IMR. 3. Create and test new and novel surgical approaches to mitral valve repair for IMR. The compelling rationale for this work is our ignorance concerning the changes in mitral leaflet shape and motion which cause IMLC and the underlying pathophysiological mechanisms within the subvalvular complex which are primarily responsible for IMLC and IMR What dilemma are we actually facing here? To quote Edmunds: "The valve is structurally normal; it need not be replaced, but currently we do not know how to fix it." The studies outlined in this application will stimulate more intelligent and rational design of refined surgical reparative techniques through a vastly improved understanding of what causes IMR. This should translate into more successful surgical treatment of this growing, life-threatening clinical problem. The proposed experiments promise to overcome our current state of mechanistic nescience, which, surprisingly, is still based largely on technological limitations. First, one cannot realistically hope to repair these morphologically normal mitral valves effectively unless we first comprehend why they leak. Second, we cannot know why IMLC and IMR occur unless one can quantitatively measure actual mitral leaflet motion and shape changes simultaneously with the 3-D dynamic geometry of the entire mitral subvalvular complex, papillary muscles, and left ventricle. We have the measurement tools and analytical capabilities to accomplish these goals, and the experimental protocols we put forward in this grant could potentially completely change our thinking about IMR and its surgical treatment.